Ultraviolet light (Uv) B-induced in-flammation is characterized by dramatic increases in prostaglandin E2 (PGE2) synthesis due to enhanced arachidonate deacylation from the membrane. Therefore, the effect of UV on synthesis, mass, and distribution of the high-molecular-weight phospholipase A2 (cPLA2) in cultured human keratinocytes and human skin was studied. The 105-kDa cPIA2 was demonstrated to be the critical enzyme in UV-induced PGE2 synthesis and erythema in the first 6 h postirradiation. Immunoprecipitation 32P-labeled protein showed cPLA2 synthesis increased three- to fourfold 6 h after irradiation. Immunoprecipitated 32P-labeled cPLA2 demonstrated phosphorylation of cPLA2 was concurrently induced, suggesting that UV also activates cPLA2. This increase in cPLA2 synthesis and activation also closely correlated with increased PGE2 synthesis and [3H]arachidonic acid release and was effectively blocked by both an S-oligonucleotide antisense to cPLA2 and methyl arachidonate fluorophosphate, a specific inhibitor of cPLA2. Biopsy and histochemical examination of irradiated sites from human volunteers revealed that only erythematous sites expressed increased amounts of cPLA2, whereas nonerythematous irradiated sites did not. In contrast, cyclooxygenase-1 and -2 in cultures and skin explants were unaffected 6 h post-UV, and no change in cyclooxygenase activity was observed at this time. These results suggest that increased cPLA2 synthesis occurs only when skin is exposed to UV doses that are sufficient to cause erythema and indicate expression of cPLA2 participates in acute UV inflammation.